Enamines generation

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

In a similar process, tertiary enaminones react with alkynylcarbene complexes to give the corresponding pyranylidene complexes following a reaction pathway analogous to that described above. First, a [2+2] cycloaddition reaction between the alkynyl moiety of the carbene complex and the C=C double bond of the enamine generates a cyclobutene intermediate, which evolves by a conrotatory cyclobutene ring opening followed by a cyclisation process [94] (Scheme 49). 

The methyl y-oxoalkanoates shown are not available by alternative methods with similar efficiency and flexibility. Although the reaction of enamines with alkyl ot-bromoacetates proceeds well in some cases, yields are only moderate in many examples.8 A further drawback is that the methods for enamine generation lack the high degree of selectivity and mildness that is characteristic of the preparation of silyl enol ethers. Related alkylations of lithium enolates often afford low yields or polyalkylated products, and are in general very inefficient when aldehydes are utilized as the starting materials.9... 

Vinylchromones undergo a [4+2]-cycloaddition with pyrrolidine enamines, generated in situ, leading to xanthones substituted in the C-ring. The reaction proceeds by way of a methylidene tetrahydroxanthone 76 (Scheme 52) <00JCS(P1)3732>. 

The regioselectivity is an issue in substrates 141. With two alkyl substituents on the distal position, tetrahydropyridines 142 are the product. With only one alkyl substituent, the cyclic imine 143 was isolated for these rearrangement products it is unknown whether they stem from the enamine generated from a 5-endo-trig or 5-exo-digcydization (Scheme 15.44) [98]. 

For determination of its configuration via a conformationally restricted cyclic derivative, A -allylamino alcohol derivative 475 was treated with tris(triphenylphosphine)rhodium(l) chloride to afford a 19 1 mixture of the C-2-epimeric tetrahydro-l,3-oxazines 476 and 477 by intramolecular trapping of the intermediate iminium species, in equilibrium with the enamine generated in the isomerization of the allyl double bond (Equation 52) <1997CC565>. 

Enamines generated from 1,3-cyclohexanedione and aminoacetaldehyde acetals can be cyclized in a one-step process by heating the components in benzene in the presence of an acid catalyst (equation 45) (78JOC3541). 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

Reaction of the tertiary amine (390) with three equivalents of dibenzoyldiimide yielded the pyrido-1,3,4-oxadiazine (391) (65%) via the intermediacy of an enamine generated from the amine (390) <77 JCS(P2) 1977 >. 

The addition of a radical to the C=C bond of enamines generates an a-amino radical, stabilized via spin delocalization onto the nitrogen atom15. The extent of this stabilization as compared to the unsubstituted methyl radical has been determined by theoretical calculations16 and experimental studies17 to be about 9-10 kcal mol-1. However, the contribution of this stability effect to the reactivity in radical addition to enamines is important only if the addition process has a late transition state, which is usually not the case for radical addition to alkenes. 

Enamines, generated in situ by iodine oxidation of tertiary amines, can react with a- or y-unsubstituted chalcogenopyrylium ions yielding the corresponding chalcogenopyranylidene iminium salts, which are easily hydrolyzed to chalcogenopyranylidene aldehydes or ketones (84JOC2676). The reaction proceeds as exemplified in Scheme 25 for 2,6-... 

It is necessary to localize the unpaired electron on a carbon atom in order to carry out direct carbon-carbon bond formation with cation radicals. One possibility is to exploit the conjugation of an unpaired electron, and enamines appeared to be suitable for this purpose. In fact, Chiba and co-workers reported that cation radicals of enamines generated by electrolysis react with anions of P-keto esters, but this type of reaction has not been studied extensively (Scheme 3). 

A proposed mechanism for the Michael addition reaction is shown in Scheme 10.7. Note that enamine, generated from the reaction of hydroxyacetone and aldolase antibody 38C2, reacts with the activated methylene group in 2-(phenyl)ethyl-2-(tri-fluoromethyl)acrylate. 

P unsaturated acids, ketones, or acyl-CoA derivatives. Highly polarized groups such as carbonyl and enamine generate electrophilic centers as indicated by the positive charges. They also affect more distant positions in conjugated systems, e.g., in a, P-unsaturated acyl-CoA derivatives, and in intermediates formed from thiamin diphosphate and pyri-doxal phosphate. 

The observations that these reactions are inhibited by nitrobenzene (a free radical inhibitor), no hydrogenated by-products are formed and that CF BrCl gives only a-CFjCl carbonyl compounds, led the authors to propose a radical chain mechanism for these reactions (Scheme 1). The chain initiation step is the formation of XFiC radical and enamine radical cation by electron transfer from the enamine to BrCFjX. The addition of this perhaloalkyl radical to the enamine generates a RjNC R R" type radical which is known to have an unusually low oxidation potential with 1/2 in the range of — 1 V (sce). An electron transfer from this radical to another molecule of perhaloalkane then takes place to form the iminium salt and another perhaloalkyl radical which continues the chain. A similar mechanism operates in the case of Rp. ... 

The addition of electron-poor radicals to enamines generates amino-substituted radicals that abstract hydrogen selectively, yielding the. vyw-products predominantly36 4 0. The size of the amino group has a moderate influence on the syn/anti ratios. 

The third subsection of this chapter discusses the a-funtionalisation of aldehydes and ketones. a-Oxidation, amination and halogenation have recently been achieved with high levels of enantioselectivity using enantiopure Lewis acids, or by generation of chiral nonracemic metal enolates, in the presence of a suitable electrophilic heteroatom source. Similar levels of selectivity in this transformation are obtained via the intermediacy of chiral enamines generated using organocatalysts. 

Utilization of a vinylogous enamine generated via 1,6-selective addition to a,p,Y,6-unsaturated iminium intermediate could potentially provide an intriguing synthetic handle for achieving greater molecular complexity. Experimental demonstration of the feasibility of this approach was provided in the development of a 1,6-selective conjugate addition/vinylogous aldol sequence catalyzed by the... 

In addition to these methods, carbon-heteroatom bond formation can also be coupled with these Heck cyclizations. One of the more straightforward methods to couple carbon-heteroatom bond formation with Heck cyclization is via enamine generation. For example, the reaction of enolizable aldehydes or ketones with 2-haloanilines provides a route to the construction of enamines for subsequent Heck cyclization. A recent example of this reaction was reported by Nazare, who demonstrated that ortho-chloroanilines can react with enolizable ketones to generate indoles (Scheme 6.54) [74]. This chemistry proceeds in good yields with a diverse variety of symmetrical and unsymmetrical ketones, provided there is only one enamine isomer, and can be applied to a range of substituted indoles. Zhu has demonstrated that enolizable aldehydes can be used in the cyclization [75]. This latter approach can provide a very effective method to selectively incorporate a range of alkyl, aryl or functionalized units into the 3-indole position, many of which are not easily accessible via other routes. 

It is believed that amine-catalyzed aldolizations, in a manner similar to class I aldolase-catalyzed reactions, proceed via a catalytic cycle that involves formation of (A) carbinolamine-, (B) iminium ion-, and (C) enamine intermediates (Scheme 4.4). Either the enamine generation or the subsequent C-C-bond-forming step (D) are rate limiting. Water addition to give a new carbinolamine (E) and its fragmentation (F) close the catalytic cycle. 

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